First we will study herpesvirus infections in transplant patients on cyclosporin A, and make clinical and pathogenetic correlations. Our second objective is to elucidate the mechanism by which cyclosporin A facilitates viral infections. We will follow our total transplant population, estimated to be about 100 renal, 30 liver and 15 heart transplants a year, for Epstein-Barr virus (EBV) infection by serology, and attemp to correlate infection with the occurrence of symptomatic infections and the development of tumors, particularly EBV-induced lymphomas. In a smaller number, all herpesvirus (cytomegalovirus, Epsetin-Barr virus, herpes simplex and varicella-zoster virus) infections as well as all other infections will be followed prospectively in the clinic and by laboratory monitors. We will study NK and K cell activity and specific cytotoxic T cell responses against CMV and EBV, and determine whether these specific cytotoxic responses are related to morbidity and mortality caused by these virus infections. The effect of dose and timing of administration of cyclosporin A on the development of specific cytotoxicity will be determined. To study the mechanism of the antiviral action of cyclosporin A, we will first concentrate on the antiviral cytotoxic response. The effect of cyclosporin A on the in vitro generation of primary and secondary cytotoxic T cells against influenza targets will be studied using mouse system. In these systems and in the system for generation of human secondary cytotoxic T cells against EBV in vitro, we will determine the effect of cyclosproin A on suppressor cells and helper cells function and on T cell growth factor production. Finally we will attempt to establish a murine CMV model in which cyclosporin A enhances acute virus infection and activates latent infection. One hypothesis to be tested will be whether suppression of cytotoxic immunity permits viral reactivation.